Metformin-Induced Generalized Bullous Fixed-Drug Eruption with a Positive Dechallenge-Rechallenge Test: A Case Report and Literature Review

Metformin is a commonly used medication in diabetic patients. It can cause different complications including cutaneous adverse reactions. Metformin-induced fixed-drug eruption (FDE) has been reported in limited cases. Due to the popularity of metformin, clinicians need to be aware of uncommon drug reactions for proper diagnosis and treatment. Herein, we report a 43-year-old man with generalized bullous lesions with a positive dechallenge-rechallenge test diagnosed as metformin-induced generalized bullous fixed-drug eruption. Metformin dosage was stopped and lesions were treated with topical clobetasol propionate and oral prednisolone and cyclosporine-A. After a 6-month follow-up, he was well without any relapsing episodes.


Introduction
Metformin is a common orally administered drug mainly used for the treatment of diabetes mellitus (DM) type 2 [1]. In addition to the control of glucose metabolism, metformin can be used for other therapeutic options such as anticancer, antiaging, protection of cardiovascular and neurologic systems, or treating polycystic ovary syndrome [2]. It has been reported as a cost-efective drug for reducing weight in obese patients [3].
Generalized bullous FDE is a rare variant of FDE, presented as classic FDE lesions involving at least 10% of the body surface area with superimposed bullae [12].
To date, six other cases have been reported with metformin-induced FDE.
Since metformin is a commonly used medication, clinicians must be aware of the unusual manifestations of this drug to provide proper diagnosis and treatment, on-time discontinuation of the drug, and avoid unnecessary further evaluation.
Herein, we report a 43-year-old man with generalized bullous lesions with a positive dechallenge-rechallenge test diagnosed as metformin-induced generalized bullous FDE.

Case Presentation
A 43-year-old man was referred with complaints of recurrent episodes of generalized bullous lesions distributed at the anterior and posterior trunk, upper and lower extremities, and genital and labial mucosa. He had started metformin about 5 years ago for losing weight. He did not have any history of DM, hypertension, or any other underlying disease. He used metformin in an irregular and   Note. Naranjo Adverse Drug Reaction Probability Scale: ≥9 � defnite adverse drug reaction; 5-8 � probable adverse drug reaction; 1-4 � possible adverse drug reaction; 0 � doubtful adverse drug reaction.  intermittent pattern. He did not use any herbal extract or other medications. Te frst time, lesions showed up two weeks after starting metformin. Lesions continued to happen in an on and of pattern with a generalized distribution.
Cutaneous examination revealed multiple well-defned erythematous to violaceous plaques with a central dusky appearance in association with bulla formation over the chest, extremities, genitalia, and lips (Figures 1(a) and 1(b)).
Due to the widespread skin denudation with clinical suspicion of generalized bullous FDE, recurrent Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and bullous pemphigoid, a punch biopsy was taken. Histopathology demonstrated vacuolar interface dermatitis, apoptotic keratinocytes, and pigment incontinence associated with eosinophil infltration that were consistent with bullous FDE (Figure 2).
Te causality assessment was carried out using the Naranjo ADR Probability Scale. Our patient's total Naranjo Scale score was 10 as a defnite adverse drug reaction [13] ( Table 1).
A diagnosis of metformin-induced generalized bullous FDE was made, and the patient was told to stop the ofending agent. After discontinuation of metformin, the progression of the disease was stopped (Figure 3) and the patient was treated with oral prednisolone (40 mg daily) and cyclosporine-A (100 mg daily). During the treatment course, the patient arbitrarily decided to rechallenge the drug. At the time he restarted the metformin, lesions became more pronounced and more severe. Tey fared up and widespread skin denudation and bullous lesions occurred with erosions and ulcers compatible with a positive rechallenge test to the metformin (Figures 1(c) and 1(d)).
Metformin again was stopped and lesions were treated with topical clobetasol propionate and oral prednisolone (60 mg daily) and cyclosporine-A (150 mg daily) and gradually tapered after clinical improvement. After a 6month follow-up, he was well without any relapsing episodes.

Discussion
Tis is the frst report of metformin-induced generalized bullous FDE with a positive dechallenge-rechallenge test in a nondiabetic patient. Presentation of generalized FDE in diabetic patients as a CADR is extremely rare. Te point that makes our case very impressive is the generalization of the bullous lesions and the long lag period for the true diagnosis.
Usually, FDE manifested as a cutaneous immunological reaction in which lesions can reappear at the same site, after re-exposure to the causative drug. Lesions can involve the lips, palms of the hands, the lower back, the hip, groin areas, and soles of the feet [10,14]. Te lesions usually appear as solitary, erythematous macules that can progress to edematous plaques or bullous-type lesions [15].
Generalized bullous fxed-drug eruptions (FDEs) are defned as blisters and erosions involving at least ten percent of the whole-body surface area and at least three of six anatomical sites [12]. An important diferential diagnosis is SJS/TEN based on the widespread distribution, dusky coloration, and skin detachment [15].
Metformin-induced FDE has been reported in six cases [10,11,14,[16][17][18] (Table 2). All of these cases are more than 40 years of age; 3 of them are female and 3 are male. Te lower limb is the most prevalent involved location (5 cases) [10,11,14,17,18]. Only one of the patients had lesions on her face [16]. Tere is no report of FDE lesions involving the trunk, but it was seen in our case for the frst time. All of the cases had a multiple drug regimen [10,11,14,[16][17][18], but in our case the only responsible drug is metformin.
Te Naranjo Scale is reported in three of the cases and ranges 5-8, which shows a probable adverse drug reaction [11,14,17]. It was measured ten in our case, which is compatible with a defnite adverse drug reaction (ADR) due to metformin ( Table 1).
Te treatment of FDE is mainly recognizing and discontinuation of the responsible drug. Also, systemic antihistamines and topical or systemic corticosteroids can be used in severe and symptomatic patients [10].
Due to its rarity, optimal treatment of generalized bullous FDE is not yet been established. Current management includes immediate cessation of the ofending drug and supportive therapy with antihistamines, analgesics, or antiseptics. Te efcacy of steroids is not proven but they are used in severe conditions [15]. In our case, metformin dosage was stopped and lesions were treated with topical clobetasol propionate, oral prednisolone, and cyclosporin.

Conclusion
Because of the potential recurrence of FDE and the clinical importance of generalized bullous FDE related to metformin, the current report provides information about a new case of generalized bullous FDE in association with metformin.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Ethical Approval
Tis study has been ethically approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (IR.ARI.MUI.REC.1401.127).

Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images.